System for transvaginal drug delivery

ABSTRACT

A transvaginal drug delivery system comprising: (a) a deposition comprising an effective amount of said drug and, optionally, a wetting agent; and (b) a polymeric support on which said deposition is deposited. Also disclosed is a catamenial tampon for insertion in a human vagina comprising: (a) an inner core comprising an absorbent material; (b) an outer layer comprising a liquid-permeable material; and (c) a delivery system according to the invention. A method of transvaginal drug delivery is also described.

FIELD OF THE INVENTION

[0001] This invention relates to a system and method for transvaginaldrug delivery.

BACKGROUND OF THE INVENTION

[0002] Transvaginal drug delivery is a well known means of administeringdrugs to a female (Woolfson, A. D., Malcolm, R. K. and Gallagher, R.(2000) Critical Reviews in Therapeutic Drug Carrier Systems 17:509-555).The transvaginal route has several advantages: (1) it is non-invasive;(2) the vagina consists of highly perfused tissue with a well-developedblood supply; (3) it avoids first-pass metabolism in the liver. Thetransvaginal route may be used both for local drug treatment as well assystemic drug absorption.

[0003] Transvaginal drug delivery systems may be classified in two maingroups: those adapted from semisolid topical systems and those designedspecifically for intravaginal use. Known systems include the following:

[0004] Mucoadhesive gels and hydrogels. These are weakly crosslinkedpolymers which are able to swell in contact with water and spread ontothe surface of mucus. These have been used for cervical ripening,spermicidal contraception, vaccination and treatment of vaginalinfections;

[0005] Vaginal tablets. They may be formulated with mucoadhesivepolymers in order to increase intravaginal residence time. They havebeen used for cervical ripening, spermicidal contraception, pregnancytermination, analgesia and urge incontinence;

[0006] Vaginal pessaries and suppositories. These are substances such asnatural gums, fatty acids, alum and rock salts which were originallyused by the ancient Egyptians as contraceptives. They have been used forcervical ripening, treatment of vaginal infections, pregnancytermination and progesterone therapy;

[0007] Microspheres for the delivery of peptide and protein drugs;

[0008] Intravaginal rings. These are torus-shaped polymeric devicesdesigned to release one or more incorporated drugs in a controlledfashion. They have been used for steroidal and spermicidalcontraception, and estrogen replacement therapy.

[0009] U.S. Pat. No. 3,918,452 (Cornfeld) discloses vaginal spongesand/or tampons impregnated with contraceptive compositions. Thecomposition comprises microcapsules containing a contraceptive drug andwhich provide sustained release of the drug before, during and/or aftercoitus.

[0010] U.S. Pat. No. 4,309,997 (Donald) discloses a medicated tampon inthe form of a soft, porous foam ball of spherical configuration. Thetampon is as impregnated with a contraceptive drug and/or an antibioticfor control of venereal disease. The tampon is inserted into the vaginato cover the cervical area while permitting intercourse to take place.

[0011] U.S. Pat. No. 5,201,326 (Kabicki et al) discloses a rod-shapedmedical tampon for releasing an active substance. The tampon includes acore of compressed fibers an a cover surrounding the core and gluedthereto, the cover comprising hardened collagen foam or hardened gelatinfoam impregnated with a retardant, such as a fatty substance, includingthe dissolved active substance to be released. The active substance maybe antibiotics, sulfonamides, antimycotics, fungicides or hormones. U.S.Pat. No. 5,417,224 (Petus et al) discloses a tampon comprising a porousspherical member having an inner region configured radially within anouter region, a cord extending through a passage extending through thespherical member, a spermicide within the pores of the inner region anda lubricant within the pores of the outer region.

[0012] U.S. Pat. No. 6,086,909 (Harrison et al) discloses devices andmethods for the treatment of dysmenorrhea which comprise an intravaginaldrug delivery system containing an appropriate pharmaceutical agentwhich is released into the vagina and absorbed through the vaginalmucosa via lymphatic and venous channels to the uterus. The drugdelivery system may include a tampon device, vaginal ring, pessary,tablet, vaginal suppository, vaginal sponge, bioadhesive tablets,bioadhesive microparticle, cream, lotion, foam, ointment, solution orgel. The system may additionally include a muco-adhesive agent and/or apenetration enhancer. In the case where the device is an absorbentvaginal tampon, one end of the tampon has a means for delivering thepharmaceutical agent while the other end has means for conveying fluiddischarged from the uterus (such as menses fluid) to the tampon, therebypreventing contact of the fluid with the agent.

[0013] Non-steroidal anti-inflammatory drugs (NSAID) are marketedworldwide as over the counter (OTC) analgesics and antipyretics, ofwhich, the most commonly used are aminophen, aspirin, ibuprofen andnaproxen.

[0014] The mechanism of most anti-inflammatory, antipyretic andanalgesic effects of NSAIDs result from the inhibition of prostaglandinsynthesis from arachidonic acid. The target of NSAID action is PGHS,which is the key rate-limiting enzyme in the production of prostanoids.This enzyme catalyzes the conversion of arachidonic acid to PGH₂ via atwo-step reaction mechanism involving sequential cyclooxygenase andperoxydase activities.

[0015] Generally, OTC analgesics are regarded as safe for the majorityof patients. However, adverse effects have been reported and are mainlyassociated with the oral administration of NSAIDs, occurring mostly inthe gastrointestinal tract. Dyspepsia appears to be the most common sideeffect, but serious adverse effects such as bleeding, ulceration andperforation can also occur. The potential of adverse renal effects havealso been reported, although for some NSAIDs this relationship remainscontroversial. Most adverse renal effects, however, are reversible onprompt discontinuation of the analgesics.

[0016] Numerous studies have dealt with the controlled release of NSAIDsfrom capsules, matrices, or gels. Colloidal liposomal carriers in aninjectable 25% poloxamer gel were used to investigate the releaseproperties of ibuprofen. Poloxamer gel was also used for the epiduralinjection of lidocaine and ibuprofen. Biodegradable matrices such aspoly lactic acid (PLA) were also used for the controlled release ofanalgesics. Gel-yielding egg albumin-based matrices were used to studydrug release kinetics. Other sustained release formulations consisted ofhydroxpropyl methylcellulose (HPMC) matrices or matrices of syntheticcrosslinked polymeric resins, as for example crosslinked poly acrylicacid.

[0017] It is estimated that 30 to 50% of the women of childbearing agein the US, are affected by painful menstrual periods or dysmenorrhea and10 to 15% of those women are incapacitated for 1 to 3 days each month.The chief symptom that women experience is spasmodic pain of the lowerabdomen, which may radiate to the back and along the thighs.

[0018] The etiology of these symptoms has been determined to be relatedto the pharmacologic actions of prostaglandin E2(PGE2) and prostaglandinF2α (PGF2α), which are formed from phospholipids of dead cell membranesin the menstruating uterus. PGE2 causes disaggregation of platelets andis a vasodilator, whereas PGF2α mediates or potentiates pain sensationsand stimulates smooth muscle contraction.

[0019] NSAIDs are successful as analgesics in 77 to 80% of dysmenorrheapatients, ibuprofen, naproxen, or naproxen sodium being the usualinitial choices.

SUMMARY OF THE INVENTION

[0020] It is an object of the invention to provide a novel deliverysystem for use with a feminine hygienic product, such as a tampon, todeliver a drug through the female vagina.

[0021] It is another object of the invention to provide a method oftransvaginal drug delivery.

[0022] In a first aspect of the invention, there is provided atransvaginal drug delivery system comprising:

[0023] (a) a deposition comprising an effective amount of the drug and,optionally, a wetting agent; and

[0024] (b) a polymeric support on which the deposition is deposited.

[0025] In the present specification, the term “transvaginal” includesboth local delivery to the vagina (intravaginal) as well as through thevagina to other target tissues in the body, including systemic effects.

[0026] The drug used in the delivery system of the invention may be anydrug which either is released and acts locally or which is absorbedthrough the vaginal mucosa to other locations in the body. Examples ofsuch drugs include non-steroidal anti-inflammatory drugs (NSAID),anti-prostaglandins, prostaglandin inhibitors, COX-2 inhibitors, localanaesthetics, calcium channel blockers, potassium channel blockers,β-adrenergic agonists, leukotriene blocking drugs, smooth muscleinhibitors, vasodilators, hormone replacement drugs, androgenic hormonesand drugs capable of inhibiting dyskinetic muscle contraction.

[0027] Non-limiting examples of NSAIDs suitable for use in the method ofthe invention include Aspirin, Ibuprofen, Indomethacin, Phenylbutazone,Bromfenac, Fenamate, Sulindac, Nabumetone, Ketorolac, and Naproxen.Examples of local anesthetics include Lidocaine, Mepivacaine,Etidocaine, Bupivacaine, 2-Chloroprocaine hydrochloride, Procaine, andTetracaine hydrochloride. Examples of calcium channel antagonistsinclude Diltiazem, Israpidien, Nimodipine, Felodipine, Verapamil,Nifedipine, Nicardipine, and Bepridil. Examples of potassium channelblockers include Defetilide, E-4031, Almokalant, Sematilide, Ambasilide,Azimilide, Tedisamil, RP58866, sotalol, Piroxicam, and Ibutilide.Examples of β-adrenergic agonists include Terbutaline, Salbutamol,Metaproterenol, and Ritodrine. Vasodilators, which are believed torelieve muscle spasm in the uterine muscle, include nitroglycerin,isosorbide dinitrate and isosorbide mononitrate. Examples of COX-2inhibitors are Celecoxib, Meloxicam and Flosulide. Examples of hormonereplacement drugs are estrogen or estradiol and progestogen. Examples ofandrogenic hormones are testosterone and other androgenic hormones.

[0028] The drug may be present in the system in combination with abiocompatible excipient or carrier acceptable for application of thedrug to the vaginal epithelium. Although the mechanism may bediffusion-controlled, the co-inclusion of excipients such as wettingagents or surfactants in the formulation, may be necessary. The term “aneffective amount” in this specification means an amount sufficient toattain a therapeutically effective amount of the drug in the targettissue or system. In a preferred embodiment, the drug is absorbablethrough the vaginal mucosa and thereby transmitted via venous andlymphatic channels to the uterus or to the general blood circulation.

[0029] The deposited drug or drug composition may include any polymercapable of producing and facilitating a coherent deposition on thepolymeric support material. Such polymers include but are not limited topolyesters, olefins, cellulose and cellulose derivatives, PVA and PVP.

[0030] The polymeric support may be any polymeric material capable ofserving as a support for the deposited material, and includes non-wovenas well as woven materials. Examples of such support material includepolypropylene, polyethylene, cellulose and cellulose derivatives or anyother polymer which can be processed as a fiber.

[0031] A preferred shape of the polymeric support is a rectangularstrip, which preferably consists of one or more layers, for example,2-16 layers. Other shapes for the strip are also contemplated as part ofthe invention.

[0032] Examples of wetting agents which may be used in the drug deliverysystem of the invention include glycerol, polyethylene glycol (PEG),polypropylene glycol (PPG) and surfactants with an HLB ranging from 10to 18 such as Tween 80. Preferred wetting agents are glycerol andPEG-8000.

[0033] The delivery system of the invention is preferably used togetherwith a catamenial tampon, as will be explained in more detail below.

[0034] Preferably, more than one delivery system will be placed in atampon on different sides, so as to release the drug in all directions.

[0035] Among the advantages of using the delivery system of theinvention for releasing a drug to the surrounding environment of thefemale urogenital tract is the contribution both to the economy of themanufacturing process of the tampon as well as to its reproducibility.In addition, the amount of drug necessary to use in the system to obtaina given effect may be significantly less than in systemic methods ofdrug administration.

[0036] In a second aspect of the invention, there is provided catamenialtampon for insertion in a human vagina comprising:

[0037] (a) an inner core comprising an absorbent material;

[0038] (b) an outer layer comprising a liquid-permeable material; and

[0039] (c) a delivery system according to the invention.

[0040] One or more of the polymeric supports or strips of the deliverysystem may be attached to the tampon, as will be described in detailbelow. Preferably, the delivery system is positioned between the innercore and the outer layer. Optionally, the tampon further comprises apolymeric water-impermeable film behind the strips of the deliverysystem, e.g. between the delivery system and the inner core. Preferably,the film is comprised of high-density polyethylene (HDPE),

[0041] In a third aspect of the invention, there is provided a method oftransvaginal drug delivery comprising inserting a catamenial tampon intoa vagina, wherein the catamenial tampon comprises:

[0042] (a) an inner core comprising an absorbent material;

[0043] (b) an outer layer comprising a liquid-permeable material; and

[0044] (c) a transvaginal drug delivery system according to theinvention.

[0045] Preferably, the drug is a NSAID such as naproxen or ibuprofen.

BRIEF DESCRIPTION OF THE DRAWINGS

[0046] In order to understand the invention and to see how it may becarried out in practice, a preferred embodiment will now be described,by way of non-limiting example only, with reference to the accompanyingdrawings, in which:

[0047]FIGS. 1a and 2 a are perspective top views of a folded-type tamponin its flat form with two different embodiments of a delivery system inaccordance with the invention;

[0048]FIGS. 1b and 2 b are perspective views of a folded-type tampon inits final folded and pressed form;

[0049]FIGS. 1c and 2 c are sectional views along lines 1 c-1 c and 2 c-2c in FIGS. 1b and 2 b, respectively;

[0050]FIGS. 3a and 4 a are perspective top views of a rolled-type tamponin its flat form with two different embodiments of a delivery system inaccordance with the invention;

[0051]FIGS. 3b and 4 b are perspective views of a rolled-type tampon inits final, rolled and pressed form; and

[0052]FIGS. 3c and 4 c are sectional views along lines 3 c-3 c and 4 c-4c in FIGS. 3b and 4 b, respectively.

[0053]FIG. 5 shows release profiles of formulated tampons containingeither 50 mg or 25 mg ibuprofen, in net enclosure permitting differentfluid volume absorption (highest release value (%), after 4 hours ofincubation, is annotated).

-50 mg. very loose net, 10 ml; ▪-50 mg. loose net, 8.9 ml; □-50 mg.tight net, 6 ml;

-25 mg tight net, 6 ml;

[0054]FIGS. 6a and 6 b show embodiments of alternate structures of thedelivery system with a polymeric film backing: a split arrangement (FIG.6a) and a continuous arrangement (FIG. 6b);

[0055]FIG. 7 shows release profiles of tampons, enclosed in a tight net,containing 100 mg of Ibuprofen and 25% glycerol with the delivery systemattached to HDPE substrate type A (results of two replicas);

[0056]FIG. 8 shows release profiles of tampons, enclosed in a tight net,containing 100 mg of Ibuprofen and 10% Tween-80 with the delivery systemattached to HDPE substrate type A (♦) and type B (); and

[0057]FIG. 9 shows release profiles of tampons, enclosed in a tight net,containing 150 mg of Ibuprofen, 20% glycerol and 20% PEG-900 (withoutHDPE substrates) (results of two replicas a (▪) and b ()).

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

[0058] I. Delivery System

[0059] The delivery system of the invention is composed of a polymericsupport, such as a non-woven polymer material, on which a deposition isdeposited. The deposition comprises a drug which may be released to thesurrounding environment. Examples of such drugs are listed above in thesummary of the invention. In one embodiment, the drug is dissolved in asolvent which is applied to the support. The deposition is deposited byevaporation of the solvent

[0060] The polymeric support is placed near the surface of the tampon.Preferably, the delivery system is positioned between the innerabsorbent core of the tampon and its outer covering layer. The polymericsupport may be in any geometrical form or shape, Preferably, the supportis in the form of rectangular strips of material, although other shapesare also possible. A plurality of these strips may be placed ondifferent sides of the tampon in order to release the drug in alldirections. In the following discussion, several non-limiting examplesare provided of tampons prepared according to the invention.

Example 1

[0061] Tampons which undergo both radial and longitudinal expansion aregenerally manufactured for use with various types of applicator devices.The longitudinal expansion is generally more than 10% of its unexpandedlength. This type of tampon comprises an inner core of absorbentmaterial, such as cellulose fibers and/or cotton fibers, enveloped by anouter layer of liquid-permeable material such as a non-woven polymer, asfor example polypropylene, polyethylene, polyester, cellulose, cellulosederivatives, or any combination of the above. This type of tampon isreferred to in this specification as a “folded-type” tampon.

[0062] A folded-type tampon according to one embodiment of the inventionis illustrated in FIG. 1a, in which can be seen a tampon 2 in its flatform comprising a body 4 and a withdrawal cord 6. The body 4 of thetampon comprises an outer layer 8 enveloping an inner absorbent core 10.The outer layer is held to the inner core in ways well known in the art,such as sewing or welding. The flat body has an upper 12 and a lower 14surface.

[0063] In this embodiment, a delivery system according to the inventionin the form of three rectangular polymeric strips are positioned betweenthe outer layer and the inner core, in parallel to the longitudinal axisof the body. One relatively wide strip 16 is on the upper surface 12 ofthe body (under the outer layer 8) and two narrow strips 18 are on thelower surface 14. The length of the strips may be approximately equal tothe length of the flat body, and preferably equal to it. Preferably, thewidth of the wide strip is approximately twice the width of the narrowstrips. Typical, non-limiting dimensions may be as follows; length andwidth of flat tampon—5-9.5 and 4-5 cm, respectively; widths of wide andnarrow strips—1.5-2.5 cm and 0.7-1.5 cm, respectively.

[0064] When the tampon is folded, it is compressed both lengthwise andwidthwise to form the conventional tampon shape, as shown in FIG. 1b.The strips 18 are aligned near the outer surface of the body of thetampon. The tampon takes on a W-like shape in cross-section, asillustrated in FIG. 1c, in which can be seen the inner core 10, theouter layer 8 and the wide 16 and narrow 18 strips below the outerlayer. It may be seen from the figure that the edges of the wide strip16 are folded within the folds of the inner core 10, thereby releasingthe drug absorbed therein to within the tampon as well as to thesurrounding environment.

Example 2

[0065] In another embodiment, illustrated in FIG. 2a, three strips arepositioned at spaced intervals between the outer layer 22 and the innercore 24 of the flat tampon 28, perpendicularly to the longitudinal axisof the flat body 26 of the tampon. In this embodiment, the strips arewound around the width of the body 26 and then excised at the lateraledges 30 of the body so that there are 3 strips 20 on the upper surface32 of the body and 3 corresponding strips 34 on the underside of thebody. The length of each of the strips is equal to the width of the flattampon. Preferably, the strips are positioned closer to the front end 36of the tampon, opposite the withdrawal cord 38, since this the end withwhich the menstrual fluid first comes into contact.

[0066] The folded tampon 40 is illustrated in FIG. 2b, in which can beseen the annular strips 20. FIG. 2c shows how the strips 20,34 appearnear the outer surface of the tampon between the outer layer 22 and theinner core 24, as well as within the folds of the inner core.

Example 3

[0067] A typical tampon which undergoes primarily radial expansion (<10%longitudinal expansion, if at all) is referred to in this specificationas a “roiled-type” tampon and is shown in FIGS. 3a-3 c. As in thefolded-type tampon described above, it comprises an inner core ofabsorbent material, as in Example 1, enveloped by an outer layer ofliquid-permeable material, as in Example 1. The rolled-type tampondiffers from the folded-type tampon, inter alia, in their dimensions aswell as in the manner of forming of the tampon. These differences affectthe placement of the strips.

[0068] As shown in FIG. 3a, the flat tampon 48 comprises an absorbentlayer 50 on which is placed an outer layer 52. The absorbent layer 50 isin the form of an extended rectangular ribbon. The material of the outerlayer 52 is generally heat sealed to the upper side of the absorbentlayer near one of its ends 54, an extension 56 of the outer layer partlyextending beyond the end 54 of the absorbent layer. The length of theextension 56 is substantially equivalent to the circumference of thetampon in its final, folded form.

[0069] According to one embodiment of the invention, three parallelspaced rectangular polymeric strips 58 are positioned equidistantly fromeach other, perpendicular to the longitudinal axis of the outer layer,and between the absorbent layer 50 and the outer layer 52. The ends ofthe strips are distanced from the longitudinal edges of the outer layer,and the strip 60 closest the end 54 of the absorbent layer is inwardlydisplaced from that end. The distance from the strip 62 farthest fromthe end 54 of the absorbent layer to that end is approximately equal tothe circumference of the tampon in its folded form.

[0070] Typical, non-limiting dimensions of the various tampon componentsare given below for exemplary purposes only: length, width and thicknessof absorbent layer—20-30 cm, 4-6 cm and 0.4-1.0 cm, respectively; lengthand width of outer layer—5-15 cm and 44.5 cm; circumference oftampon—34.5 cm; length of strips —3.5-5.5 cm.

[0071]FIG. 3b shows the tampon 64 in its folded form comprising the body66 and withdrawal cord 68. During the forming process, the absorbentlayer of the flat tampon (FIG. 3a) is rolled up onto itself along itslongitudinal axis towards the end on which the strips and outer layerare placed, and the extension 56 of the outer layer is heat welded tothe opposite end of the outer layer, thus enveloping the absorbent layerwhich now forms the core of the tampon. Two of the three strips 58 maybe seen in FIG. 3b through the outer layer, with the third strip out ofsight behind the body of the tampon. FIG. 3c shows the three componentsof the tampon according to the invention: the rolled up inner absorbentcore 50, the outer layer 52 and the strips 58.

Example 4

[0072] In this embodiment, illustrated in FIGS. 4a-4 c, the strips areplaced parallel to the longitudinal axis of the outer layer rather thanperpendicular thereto. Thus, FIG. 4a illustrates the absorbent layer 60and outer layer 62 of the flat tampon 63 as in the previous example.Three parallel equidistant strips 64 are placed between the two layersin parallel to the longitudinal axis of the outer layer. The length ofeach strip is equal to the circumference of the tampon in its finalform. Preferably, the strips are placed proximate to the anterior end ofthe folded tampon.

[0073]FIGS. 4b and 4 c show the tampon 66 in its folded form comprisingthe inner core 60, the outer layer 62 and the strips 64.

[0074] II. In vitro Experiments

[0075] A. Introduction

[0076] The following is a summary of the main results and conclusions ofin vitro release studies, conducted with two selected NSAIDs, Naproxenand Ibuprofen, using the delivery system of the invention.

[0077] Due to the relatively hydrophobic nature of Naproxen andIbuprofen, special attention should be given to the potential extent ofbioavailability of the drugs, from the formulated tampons as a result ofthe small fluid volume in the vagina during menstruation (5-8 ml). Theavailability of the drugs is mainly governed by two processes: Vaginalmucosa tissue penetration, which in this case is not considered alimiting factor, and the release pattern of the drugs from theformulated tampons, the dependence of which is mainly affected by drugaqueous solubility and diffusion.

[0078] Normally, in the case of in vitro release studies of relativelyhydrophobic drugs with good tissue penetration, the experiments areconducted under “SINK conditions”. The term SINK conditions originatedfrom the fact that the drug concentration gradient between the externaland internal epithelial layer is always maximal, and that the tissue orblood acts as a natural ‘sink’, i.e. the drug is instantaneouslyabsorbed the moment it dissolves. Therefore, under in vivo conditions,there is no concentration buildup and hence the retarding effect of lowand/or moderate concentration gradient in unlikely to occur. In order tosimulate the in vivo sink conditions, in vitro dissolution or releasekinetics studies are usually conducted using a large volume ofdissolution or release medium, so that the solute concentration neverreaches more than 5-10% of its maximum solubility under identicalexperimental conditions. If such conditions are maintained, the lowaqueous solubility of the drug does not represent anymore arate-limiting factor. All in vitro tests in this specification wereconducted under sink conditions using 10% of maximum solubilityconcentration, unless otherwise specified.

[0079] B. Materials and Methods

[0080] Materials:

[0081] Both drugs were kindly provided by Teva Pharmaceuticals, Ltd.,Israel, and are of pharmacopoeia grade. All other ingredients used inthe study were analytical or HPLC grade.

[0082] Methods:

[0083] 1. Preparation of Delivery System:

[0084] Based on previous knowledge, the following formulation wasretained: each one of the drugs was first dissolved in ethanol, at aconcentration determined by the drug dosage per tampon, and glycerol wasadded to a percentage of 15% calculated on drug weight basis. Glycerolacts as a wetting agent. The co-inclusion of other wetting agents orsurfactants in the formulation may be necessary at times. Theformulation was loaded on non-woven (NW) strip (7.5-8.5×2.5 cm) (i.e.the delivery system), by immersing the NW in an ethanol solution,containing the formulation, and eventually evaporating the solvent. Bothethanol and acetone were found suitable for this method, nevertheless,ethanol was chosen due to its significantly lower toxicity.

[0085] The formulation-containing strips of the folded-type were folded2 times around the axial direction and 7.5 cm-long strips were preparedby pressing the folded material at 1 ton/cm² for 30 seconds. 4 layeredstrips were obtained by using a single PP/PE (NW). One 2.5 cm strip andtwo 1.25 cm strips were attached to a tampon in the longitudinaldirection as shown in FIG. 1a.

[0086] The dose preliminarily chosen, was 50 mg of the drug per tamponand was compared with different lower and higher doses, in terms ofrelease pattern efficiency. For simplicity and clarity reasons, the twodrugs chosen for this study are dealt with separately.

[0087] 2. Release of Ibuprofen: In vitro Release Kinetics Conditions:

[0088] SINK Conditions:

[0089] The release medium used for these experiments was theSorensen-Walbum buffer, chosen here due to its lack of absorbance in theUV range, thus causing less interference with the analytical drugdetection process. The buffer consisted of glycine (0.1 M) and NaCl (0.1M), adjusted to pH 7.4 with NaOH (0.1 M).

[0090] In order to establish SINK conditions, the saturationconcentration of Ibuprofen, under the release conditions, wasdetermined. A large excess of Ibuprofen was added to 50 ml of theSorensen buffer and agitated in a sealed flask at 37° C., for a periodof 24 hours

[0091] The saturation concentration of Ibuprofen under these conditions,as determined by HPLC, was 100 μg/ml. Accordingly, the SINK conditionsconcentration was set to 10 μg/ml. It is worth mentioning that asignificantly higher saturation concentration can be reached by firstdissolving the drug in a small quantity of ethanol and then mixing itwith the buffer solution. Nevertheless, these are not the conditionsunder which the drug is released in vitro or in vivo.

[0092] 3. HPLC Method for Ibuprofen Determination:

[0093] Ibuprofen concentrations were determined by means of highperformance liquid chromatography (HPLC), using the method described inPharmaceutical Research (1998) 15:482487.

[0094] Column: RP-C₁₈, 5 μm, 25 cm, (Merck) at ambient temperature.

[0095] Flow rate: 2 ml/min.

[0096] Isocratic mobile phase: acetonitrile: 0.1 M sodium acetate (35:65v/v), adjusted to pH 6.2 with glacial acetic acid.

[0097] UV detector at 222 nm.

[0098] Detection limit: 0.05 μg/ml.

[0099] The linear relation of peak area to calibration concentrationsobtained in a concentration range of 0-2000 μg/ml was linear and yieldedan r value higher than 0.99.

[0100] 4. Release of Naproxen: In vitro Release Kinetics Conditions

[0101] SINK Conditions:

[0102] In order to establish sink conditions, the saturationconcentration of Naproxen, under the release kinetics experimentalconditions, was determined, in the same manner as described before forIbuprofen. A large excess of Naproxen was added to 50 ml of the Sorensenbuffer and agitated in a sealed flask at 37° C., for a period of 24hours.

[0103] The saturation concentration of Naproxen under these conditions,as determined by HPLC, was 109 μg/ml, only slightly higher than that ofIbuprofen. Accordingly, the sin conditions concentration was set to 10.9μg/ml, which is 10% of the saturation conditions.

[0104] 5. HPLC Method:

[0105] Naproxen concentrations were determined by HPLC using the methoddescribed in Acta Phanniacol. et Toxicol. (1980) 47:267-273.

[0106] Column: RP-C₁₈, 5 μm 25 mm, (Merck) at ambient temperature.

[0107] Flow rate: 2 ml/min.

[0108] Isocratic mobile phase: acetonitrile: 100 mM aimnonium acetate(40:60 v/v), adjusted to pH 5.5 with glacial acetic acid.

[0109] UV detector at 280 nm.

[0110] Detection limit: 0.02 μg/ml.

[0111] The linear relation of peak area to calibration concentrationsobtained in a concentration range of 0-2000 μm/ml was linear and yieldedan r value higher than 0.99.

[0112] Results

[0113] 1. Fluid Absorption

[0114] Formulated tampons (with either ibuprofen or naproxen) wereenclosed in a flexible plastic net. The net was firmly tied around thetampons, so that it allowed a maximum absorption of 6 ml of the releasemedium, which is close to the absorption volume of menstrual fluidsunder physiological conditions. For comparison purposes, the extent ofnet tightness was decreased to allow a final absorption volume of 8-10ml.

[0115]FIG. 5 summarizes the ibuprofen release results obtained comparingthe effect of two parameters—fluid absorption and amount offormulation—on the drug release profile.

[0116] Although some effect of the formulation amount is observed, themost significant factor influencing the release profile is the fluidabsorption volume. Increasing the absorption volume from 6 ml to 8.9 mland finally to 10 ml, led to an increase in drug release from 32% to 61%and to 97%, respectively.

[0117] At this stage, it was concluded that the drug release rate from atampon will markedly depend on the fluid absorption. It is worthmentioning though, that in vitro the fluid absorption was mainlygoverned by the expansion ability of the tampon, which was restricted bythe net enclosure. Under in vivo conditions, however, the tampon is in asignificantly more expanded form with the same fluid absorption volume.

[0118] 2. Release Studies of Naproxen from Tampons Containing a DeliverySystem Attached to HDPE Substrates:

[0119] In an attempt to enhance the drug release kinetics, theformulated delivery system was attached to a thin film of high-densitypolyethylene (HDPE) which is a relatively inert and hydrophobicmaterial, impermeable to water. The main concept of placing a thin HDPEsubstrate attached to the formulated chip was to facilitate the outwarddiffusion of the drug by minimizing the inward flow. The HDPE substratewas attached to the delivery system by sewing the edges with a cottontread. The chip was mounted on the tampon with the HDPE substrate facinginward.

[0120] Two different approaches were tested. In one approach(type-A—FIG. 6a), a split HDPE substrate 70 was used, being onlyslightly larger than each of the formulated NW strips 72. In the secondapproach (type-B—FIG. 6b), a continuous substrate 74 was used coveringalmost the total area on each side of the tampon behind the formulatedNW strips 76. A loose net enclosure was used, allowing a maximum fluidabsorption of 10 ml.

[0121] 3. Release Studies of Ibuprofen from Tampons in anAlbumin-containing Release Medium

[0122] Among the various parameters tested, it is the drug solubilityand possibly its diffusion pattern that constitute the principlelimiting factors in the drug release process. Thus, it was consideredthat the use of the Sorensen buffer alone as a release medium might notclosely enough resemble the physicochemical properties of the menstrualfluid, in terms of drug dissolution.

[0123] Consequently, a plasma protein-albumin—was dissolved in theSorensen buffer at a concentration of either 1% or 3%, the latter beingthe actual albumin concentration in the blood.

[0124] 4. Measurement of Saturation Concentration—Determination of SINKConditions:

[0125] An excess amount of drug (Ibuprofen) was added to 30 ml ofSorensen buffer (pH 7.4), containing either 1% or 3% of dissolvedalbumin, and agitated in sealed flasks at 37° C., for a period of 24h.The solution concentration was determined by HPLC.

[0126] The saturation concentrations obtained with the 1% and 3% albumincontaining buffer solutions were approximately 730 μm/ml and 2100 μg/ml,respectively. These concentrations are respectively 7 to 21 times higherthan the 100 μg/ml saturation concentration obtained with the Sorensenbuffer alone. It is believed that either a complexation process betweenthe protein and drug molecules, or a change in the solubility parametersof the solution led to such a significant increase in the drugsaturation concentration.

[0127] SINK conditions were set at 6.8% and 14% for formulated tamponscontaining 50 mg and 100 mg of ibuprofen, respectively, in a volume of 1liter of releasing medium containing 1% bovine serum albumin.

[0128] 5. In vitro Drug Release Procedure:

[0129] The in vitro experimental conditions were set as follows: Dragrelease from formulated tampons was performed in a dissolutionapparatus, consisting of 6 1-liter glass vessels immersed in acontrolled temperature water bath and equipped with a controlledmechanical stirring system (130 rpm). Albumin concentration in thereleasing medium was 1% and the solution was kept at a constanttemperature of 37° C.

[0130] Formulated tampons were enclosed in a tight plastic net,restricting the maximum fluid absorption to 5-6 ml. The tampons wereimmersed into the releasing medium head down, held vertically by thestring. A small glass weight was attached to the tampon, in order toprevent floating. All experiments were carried out in two replicas.Samples were taken in duplicates and treated as described in theprevious section.

[0131] Following the release process, the tampons were washed with 50 mlof ethanol in order to extract the residual amounts of drug present inthe tampon at the end of the process. The sum of the residual and thereleased amounts was considered as the total amount of drug originallypresent in the formulated tampon. The percent of drug release was thuscalculated.

[0132] 6. Release Studies Results:

[0133] Among the different formulations previously tested three versionswere selected and compared under the new experimental conditions. Theseformulations differed in several parameters, i.e. the amount of drug pertampon, the type and amount of wetting agent, and the presence orabsence of an HDPE substrate attached to the inner side of theformulated delivery system mounted on the tampons.

[0134] The selected formulations were as follows:

100 mg Ibuprofen*+25% glycerol; split HDPE substrate  (a)

100 mg Ibuprofen*+10% Tween 80, split HDPE substrate  (b)

100 mg Ibuprofen*+10% Tween 80; continuous HDPE substrate  (c)

150 mg Ibuprofen*+20% glycerol+20% PEG 1000; no HDPE *amounts pertampon  (c)

[0135] The release profiles of the different formulated tampons, arepresented in FIGS. 7, 8 and 9.

[0136] The release profile of formulation number (a), under tight netenclosure conditions, is depicted in FIG. 7. It can clearly be observed,that most of the formulation is released within the first 2 hours. Therelease profiles of formulation numbers (b) and (c), shown in FIG. 8clearly indicate that the use of Tween 80 as wetting agent instead ofglycerol, does not increase the release rate and even slows it down. Nosignificant difference in the release profiles was observed when usingeither split or continuous HDPE substrates.

[0137] Finally, it can be noted from FIG. 9 that the release profile ofthe drug from a tampon including glycerol and PEG-1000 as wetting agentsand no HDPE substrate (formulation (d)) was markedly reduced. Only50-60% of the drug was released within 120 minutes, as compared to theapproximately 80% of the drug which were released within the same periodof time when using an HDPE substrate (FIG. 7), It is therefore suggestedthat the use of an HDPE substrate does promote and increase the rate ofdrug release.

1. A transvaginal drug delivery system comprising: (a) a depositioncomprising an effective amount of said drug and, optionally, a wettingagent; and (b) a polymeric support on which said deposition isdeposited.
 2. A delivery system according to claim 1 wherein said drugis selected from the following: nonsteroidal anti-inflammatory drug(NSAID), anti-prostaglandin, prostaglandin inhibitor, COX-2 inhibitor,local anaesthetic, calcium channel blocker, potassium channel blocker,β-adrenergic agonist, leukotriene blocking agent, smooth muscleinhibitor, vasodilator, hormone replacement drug, androgenic hormone anda drug capable of inhibiting dyskinetic muscle contraction.
 3. Adelivery system according to claim 2 wherein said NSAID is selected fromthe following: Aspirin, Ibuprofen, Indomethacin, Phenylbutazone,Bromfenac, Fenamate, Sulindac, Nabumetone, Ketorolac, and Naproxen; saidlocal anesthetic is selected from the following: Lidocaine, Mepivacaine,Etidocaine, Bupivacaine, 2-Chloroprocaine hydrochloride, Procaine, andTetracaine hydrochloride; said calcium channel antagonist is selectedfrom the following: Diltiazem, Israpidien, Nimodipine, Felodipine,Verapamil, Nifedipine, Nicardipine, and Bepridil; said potassium channelblocker is selected from the following: Defetilide, E-4031, Almokalant,Sematilide, Ambasilide, Azimilide, Tedisamil, RP58866, sotalol,Piroxicam, and Ibutilide; said β-adrenergic agonist is selected from thefollowing: Terbutaline, Salbutamol, Metaproterenol, and Ritodrine; saidvasodilator is selected from the following: nitroglycerin, isosorbidedinitrate and isosorbide mononitrate; said hormone replacement drug isselected from the following: estrogen or estradiol and progestogen; saidandrogenic hormone is selected from the following: testosterone andother androgenic hormones; said COX-2 inhibitor is selected from thefollowing: Celecoxib, Meloxicam and Flosulide; and derivatives of any ofthe above drugs.
 4. A delivery system according to claim 3 wherein saidNSAID is naproxen or ibuprofen.
 5. A delivery system according to claim1 wherein the components of said deposition are dissolved in a solventand the deposition is deposited by evaporation of said solvent.
 6. Adelivery system according to claim 1 wherein said polymeric supportcomprises a non-woven polymer.
 7. A delivery system according to claim 1wherein said polymeric support is in the form of a strip.
 8. A deliverysystem according to claim 7 wherein said strip consists of one or morelayers.
 9. A delivery system according to claim 8 wherein said stripconsists of 2-16 layers.
 10. A catamenial tampon for insertion in ahuman vagina comprising: (a) an inner core comprising an absorbentmaterial; (b) an oater layer comprising a liquid-permeable material; and(c) a delivery system according to claim
 1. 11. A tampon according toclaim 10 wherein said delivery system is positioned between said innercore and said outer layer.
 12. A catamenial tampon according to claim 11further comprising a polymeric water-impermeable film between saiddelivery system and said inner core.
 13. A tampon according to claim 10wherein said delivery system comprises a plurality of strips of thepolymeric support.
 14. A tampon according to claim 13 comprising 3strips.
 15. A catamenial tampon according to claim 10 further comprisinga polymeric water-impermeable film behind said delivery system.
 16. Acatamenial tampon according to claim 15 wherein said polymericwater-impermeable film comprises high-density polyethylene (HDPE).
 17. Amethod of transvaginal drug delivery comprising inserting a catamenialtampon into a vagina, wherein said catamenial tampon comprises: (a) aninner core comprising an absorbent material; (b) an outer layercomprising a liquid-permeable material; and (c) a delivery systemaccording to claim
 1. 18. A method according to claim 17 wherein saiddrug is a NSAID.
 19. A method according to claim 18 wherein said NSAIDis naproxen or ibuprofen.